The present invention relates to novel thieno[3,2-d]pyrimidine and furo[3,2-d]pyrimidine derivatives and their use in therapy. In particular, the present invention relates to the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial. The invention relates in particular to adenosine receptors and particularly adenosine A2A receptors, and to the treatment of movement disorders such as Parkinson""s disease.
Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson""s disease, Alzheimer""s disease, Huntington""s chorea and Wilson""s disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
There are four classic symptoms of Parkinson""s disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson""s disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson""s disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson""s disease are manifested.
Current strategies for the treatment of Parkinson""s disease are based on transmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)), inhibition of monoamine oxidase (e.g. Deprenyl(copyright)), dopamine receptor agonists (e.g. bromocriptine and apomorphine) and anticholinergics (e.g. benztrophine, orphenadrine). Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when xe2x80x9con-offxe2x80x9d symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chores, nausea and vomiting. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients. Despite new drug approvals, there is still a medical need in terms of improved therapies for movement disorders, especially Parkinson""s disease. In particular, effective treatments requiring less frequent dosing, effective treatments which are associated with less severe side-effects, and effective treatments which control or reverse the underlying neurodegenerative disorder, are required.
Blockade of A2 adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson""s disease (Richardson, P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61-65). The potential utility of adenosine A2A receptor antagonists in the treatment of movement disorders such as Parkinson""s Disease has recently been reviewed (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320).
Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects. The central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., J. Med. Chem. 1992, 35, 407-422). This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S. S.; Williams, M. Exp. Opin. Ther. Patents 1995, 5,547-558).
Adenosine receptors represent a subclass (P1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as A1, A2A, A2B (of high and low affinity) and A3 (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156). The adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128).
The design of P1 receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707-722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson""s disease (Williams, M. and Burnstock, G. Purinergic Approaches Exp. Ther. (1997), 3-26. Editor: Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)
The pharmacology of adenosine A2A receptors has been reviewed (Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10), 364-372). One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A2 adenosine receptors is the evidence of a functional link between adenosine A2A receptors to dopamine D2 receptors in the CNS. Some of the early studies (e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc. Nal. Acad. Sci. U.S.A. 1991, 88, 7238-41) have been summarised in two more recent articles (Fuxe, K. et al., Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., [Proc. Int. Symp.], 5th (1995), 499-507. Editors: Belardinelli, Luiz; Pelleg, Amir. Publisher: Kluwer, Boston, Mass.; Ferre, S. et al., Trends Neurosci. 1997, 20, 482-487).
As a result of these investigations into the functional role of adenosine A2A receptors in the CNS, especially in vivo studies linking A2 receptors with catalepsy (Ferre et al., Neurosci. Lett. 1991, 130, 162-4; Mandhane, S. N. et al., Eur. J. Pharmacol. 1997, 328, 135-141) investigations have been made into agents which selectively bind to adenosine A2A receptors as potentially effective treatments for Parkinson""s disease.
While many of the potential drugs for treatment of Parkinson""s disease have shown benefit in the treatment of movement disorders, an advantage of adenosine A2A antagonist therapy is that the underlying neurodegenerative disorder may also be treated. The neuroprotective effect of adenosine A2A antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Ann. N. Y. Acad. Sci. 1997, 825(Neuroprotective Agents), 30-48).
Xanthine derivatives have been disclosed as adenosine A2 receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A2 receptors, such as Parkinson""s disease (see, for example, EP-A-565377).
One prominent xanthine-derived adenosine A2A selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993, 323, 141-144).
Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A1 and A2A receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in Parkinson""s disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophylline levels of 4.44 mg/L after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W. J. Pharm. Pharmacol. 1994, 46, 515-517).
KF 17837 [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] is a selective adenosine A2A receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine. Moreover, KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A2A receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268). The structure activity relationship (SAR) of KF 17837 has been published (Shimada, J. et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352). Recent data has also been provided on the A2A receptor antagonist KW-6002 (Kuwana, Y et al., Soc. Neurosci. Absir. 1997, 23, 119.14; and Kanda, T. et al., Ann. Neurol. 1998, 43(4), 507-513).
New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective A2A Adenosine Antagonists. J. Med. Chem. 1996, 39, 1164-71). SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70) and has been followed up by a later series of compounds (Baraldi, P. G. et al., J. Med. Chem. 1998, 41(12), 2126-2133).
The foregoing discussion indicates that a potentially effective treatment for movement disorders in humans would comprise agents which act as antagonists at adenosine A2A receptors.
It has now been found that novel thieno[3,2-d]pyrimidine and furo[3,2-d]pyrimidine derivatives, which are structurally unrelated to known adenosine receptor antagonists, exhibit unexpected antagonist binding affinity at adenosine (P1) receptors, and in particular at the adenosine A2A receptor. Such compounds may therefore be useful for the treatment of disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial. In particular such compounds may be suitable for the treatment of movement disorders, such as disorders of the basal ganglia which result in dyskinesias. These may include Parkinson""s disease, Alzheimer""s disease, spasticity, Huntington""s chorea and Wilson""s disease.
According to the present invention there is provided a compound of formula (I): 
wherein:
X is O or S;
R1 and R2 are independently selected from hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, cyano, nitro, CO2R7, COR7, OCOR7, CONR7R8, CONR7NR8R9, OCONR7R8, NR7R9, NR7COR8, NR7CONR8R9, NR7CO2R8, NR7SO2R8, NR7CONR8NR9R10, NR7NR8CO2R9, NR7NR8CONR9R10, NR7SO2NR8R9, SO2R7, SOR7, SR7 and SO2NR7R8, or R1 and R2 together form a carbonyl group (Cxe2x95x90O), an oxime group (Cxe2x95x90NOR11), an imine group (Cxe2x95x90NR11) or a hydrazone group (Cxe2x95x90NNR11R12), or R1 and R2 together form a 5, 6 or 7 membered carbocyclic or heterocyclic ring;
R3 is alkyl or aryl;
R4, R5 and R6 are independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, nitro, cyano, alkoxy, aryloxy, COR7, OCOR7, CO2R7, SR7, SOR7, SO2R7, SO2NR7R8, CONR7R8, CONR7NR8R9, OCONR7R8, NR7R8, NR7COR8, NR7CONR8R9, NR7CO2R8, NR7SO2R8, CR7xe2x95x90NOR8, NR7CONR8NR9R10, NR7NR8CO2R9, NR7NR8CONR9R10, SO2NR7NR8R9, NR7SO2NR8R9, NR7NR8SO2R9, NR7NR8COR9, NR7NR8R9 and NR7CSNR8R9, or R5 and R6 together form a 5, 6 or 7 membered carbocyclic or heterocyclic ring; and
R7, R8, R9, R10, R11 and R12 are independently selected from hydrogen, alkyl and aryl,
or a pharmaceutically acceptable salt thereof or prodrug thereof.
As used herein, the term xe2x80x9calkylxe2x80x9d means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic, the alkyl group is preferably C3 to C12, more preferably C5 to C10, more preferably C5, C6 or C7. Where acyclic, the alkyl group is preferably C1 to C10, more preferably C1 to C6, more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl. It will be appreciated therefore that the term xe2x80x9calkylxe2x80x9d as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl and cycloalkynyl.
As used herein, the term xe2x80x9clower alkylxe2x80x9d means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
As used herein, the term xe2x80x9carylxe2x80x9d means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more heteroatom, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl isoxazolyl, pyrazolyl, triazolyl, imidazolyl or pyrimidinyl.
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94. As used herein, the term xe2x80x9caryloxyxe2x80x9d means aryl-Oxe2x80x94.
As used herein, the term xe2x80x9chalogenxe2x80x9d means a fluorine, chlorine, bromine or iodine radical.
As used herein the term xe2x80x9cR1 and R2 together form a carbonyl group, an oxime group, an imine group or a hydrazone groupxe2x80x9d means that R1 and R2 in combination with the carbon atom to which they are bound together form a carbonyl group, an oxime group, an imine group or a hydrazone group, i.e. the carbon atom to which R1 and R2 are bound in formula (I) is attached via a double bond to an oxygen atom (for compounds wherein R1 and R2 together form a carbonyl group) or to a nitrogen atom (for compounds wherein R1 and R2 together form an oxime, imine or hydrazone group).
As used herein the term xe2x80x9coxime groupxe2x80x9d means a group of formula Cxe2x95x90Nxe2x80x94OR11 where R11 is selected from hydrogen, alkyl and aryl.
As used herein the term xe2x80x9cimine groupxe2x80x9d means a group of formula Cxe2x95x90Nxe2x80x94R11 where R11 is selected from hydrogen, alkyl and amyl.
As used herein the term xe2x80x9chydrazone groupxe2x80x9d means a group of formula Cxe2x95x90Nxe2x80x94NR11R12 where R11 and R12 arm independently selected from hydrogen, alkyl and aryl.
As used herein, the term xe2x80x9cprodrugxe2x80x9d means any pharmaceutically acceptable prodrug of a compound of the present invention.
According to the first embodiment of the invention, alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. According to the first embodiment of the invention, substituents may include:
carbon-containing groups such as
alkyl
aryl, (e.g. substituted and unsubstituted phenyl),
arylalkyl; (e.g. substituted and unsubstituted benzyl);
halogen atoms and halogen containing groups such as
haloalkyl (e.g. trifluoromethyl),
haloaryl (e.g. chlorophenyl);
oxygen containing groups such as
alcohols (e.g. hydroxy, hydroxyalkyl, hydroxyaryl, (aryl)hydroxy)alkyl),
ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, alkoxyaryl aryloxyaryl),
aldehydes (e.g. carboxaldehyde),
ketones (e.g. alkylcarbonyl, arylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaryl, arylcarbonylalkyl, arylcarbonylaryl, arylalkylcarbonyl, arylalkylcarbonylalkyl, arylalkylcarbonylaryl)
acids (e.g. carboxy, carboxyalkyl, carboxyaryl),
acid derivatives such as esters
xe2x80x83(e.g. alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylcarbonyloxy, alkylcartonyloxyalkyl), amides
xe2x80x83(e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl or arylalkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino or arylalkylcarbonylamino), carbamates
xe2x80x83(eg. alkoxycarbonylamino, aryloxycarbonylamino, arylalkyloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, arylaminocarbonyloxy or arylalkylaminocarbonyloxy) and ureas
xe2x80x83(eg. mono- or di-alkylaminocarbonylamino, arylaminocarbonylamino or arylalkylaminocarbonylamino);
nitrogen containing groups such as
amines (e.g. amino, mono- or dialkylamino, arylamino, aminoalkyl, mono- or dialkylaminoalkyl),
azides,
nitriles (e.g. cyano, cyanoalkyl),
nitro;
sulfur containing groups such as
thiols, thioethers, sulfoxides, and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl)
and heterocyclic groups containing one or more, preferably one, heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).
According to the second embodiment of the invention, alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. According to the second embodiment of the invention, the substituent groups are selected from:
carbon containing groups such as
alkyl,
aryl,
arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl);
halogen atoms and halogen containing groups such as
haloalkyl (e.g. trifluoromethyl);
oxygen containing groups such as
alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl),
ethers (e.g. alkoxy, alkoxyalkyl, aryloxyalkyl),
aldehydes (e.g. carboxaldehyde),
ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl)
acids (e.g. carboxy, carboxyalkyl),
acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl)
and amides (e.g. aminocarbonyl, mono- or dialkylaminocarbonyl, aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl, arylaminocarbonyl);
nitrogen containing groups such as
amines (e.g. amino, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl),
azides,
nitriles (e.g. cyano, cyanoalkyl),
nitro;
sulfur containing groups such as
thiols, thioethers, sulfoxides, and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl);
and heterocyclic groups containing one or more, preferably one, heteroatom (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).
According to the third embodiment of the invention, where any of R1 to R12 is selected from alkyl and alkoxy, in accordance with formula (I) as defined above, then that alkyl group, or the alkyl group of the alkoxy group, may be substituted or unsubstituted. Where any of R1 to R12 are selected from aryl and aryloxy, in accordance with formula (I) as defined above, then said aryl group, or the aryl group of the aryloxy group, may be substituted or unsubstituted. Where R1 and R2 together form a carbocyclic or heterocyclic ring, or R5 and R6 together form a carbocyclic or heterocyclic ring, in accordance with formula (I) as defined above, then that carbocyclic or heterocyclic ring may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. In the third embodiment of the invention, the substituents are those defined in respect of the second embodiment of the invention described above.
According to the fourth embodiment of the invention, where any of R1 to R12 is selected from alkyl and alkoxy, in accordance with formula (I) as defined above, then that alkyl group, or the alkyl group of the alkoxy group, may be substituted or unsubstituted. Where any of R1 to R12 are selected from aryl and aryloxy, in accordance with formula (I) as defined above, then said aryl group, or the aryl group of the aryloxy group, may be substituted or unsubstituted. Where R1 and R2 together form a carbocyclic or heterocyclic ring, or R5 and R6 together form a carbocyclic or heterocyclic ring, in accordance with formula (I) as defined above, then that carbocyclic or heterocyclic ring may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. In the fourth embodiment of the invention, the substituents may include those defined in respect of the first embodiment of the invention described above.
According to the fifth embodiment of the invention, the compounds are selected from compounds of formula (Ia): 
wherein X, R1 to R3 and R5 to R12 are as defined for formula (I) above;
R4 is selected from hydrogen, alkyl, aryl, halogen, hydroxy, nitro, cyano, alkoxy, aryloxy, COR7, OCOR7, CO2R7, SR7, SOR7, SO2R7, SO2NR7R8, CONR7R8, CONR7NR8R9, CONR7YNR8R9, OCONR7R8, NR7R8, NR7YR8, NR7COR8, NR7CONR8R9, NR7ZCONR8R9, NR7CO2R8, NR7ZCO2R8, N(COR8)COR9, NR7SO2R8, CR7xe2x95x90NOR8, NR7CONR8N9R10, NR7CONR8YNR9R10, NR7NR8COR9, NR7YNR8C2R9, NR7NR8CONR9R10, NR7YNR8CONR9R10, SO2NR7NR8R9, SO2NR7YNR8R9, NR7SO2NR8SR9, NR7NR8O2R9, NR7YNR8SO2R9, NR7NR8COR9, NR7YNR8COR9, NR7NR8R9, NR7YNR8R9, NR7CSNR8R9, NR7YNR8CSNR9R10 and NR7YNR8CONR9YNR10R11);
Y is a divalent C2 to C4 carbon chain; and
Z is a divalent C1 to C4 carbon chain,
or a pharmaceutically acceptable salt thereof or prodrug thereof.
In the fifth embodiment of the invention, where any of R1 to R12 is selected from alkyl and alkoxy, in accordance with formula (Ia) as defined above, then that alkyl group, or the alkyl group of the alkoxy group, may be substituted or unsubstituted. Where any of R1 to R12 are selected from aryl and aryloxy, in accordance with formula (Ia) as defined above, then said aryl group, or the aryl group of the aryloxy group, may be substituted or unsubstituted. Where R1 and R2 together form a carbocyclic or heterocyclic ring, or R5 and R6 together form a carbocyclic or heterocyclic ring, in accordance with formula (Ia) as defined above, then that carbocyclic or heterocyclic ring may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. In the fifth embodiment of the invention, the substituents may include those defined in respect of the first embodiment of the invention described above.
As used herein, the term xe2x80x9cdivalent C1 to C4 carbon chainxe2x80x9d means a chain comprising 1, 2, 3 or carbon atoms, branched or unbranched, and saturated or unsaturated.
As used herein, the term xe2x80x9cdivalent C2 to C4 carbon chainxe2x80x9d means a chain comprising 2, 3 or 4 carbon atoms, branched or unbranched, and saturated or unsaturated.
In the compounds of the present invention, preferably X is S.
In a preferred embodiment of the invention, R1 and R2 are independently selected from hydrogen; hydroxy; cyano; alkyl, preferably hydroxy-substituted alkyl; and CO2R7, wherein preferably R7 is alkyl. In this embodiment, it is preferred that R1 and R2 are selected from hydrogen and cyano. In this embodiment, it is preferred that one of R1 and R2 is hydrogen.
In a further embodiment, where R1 is hydroxy, R2 is not selected from hydroxy, alkoxy and aryloxy. Similarly, where R2 is hydroxy, it is preferred that R1 is not selected from hydroxy, alkoxy and aryloxy.
In an alternative further embodiment, where R1 is selected from hydroxy and SH, R2 is not selected from hydroxy, alkoxy, aryloxy and SR7. Similarly, where R2 is selected from hydroxy and SH, it is preferred that R1 is not selected from hydroxy, alkoxy, aryloxy and SR7.
In a preferred embodiment, R1 and R2 together form a carbonyl group or an oxime group, preferably a carbonyl group. Where R1 and R2 together form an oxime group Cxe2x95x90Nxe2x80x94OR11, it is preferred that R11 is hydrogen
In a particularly preferred embodiment of the invention, R1 and R2 together form a carbonyl group.
In the compounds of the present invention, it is preferred that R3 is aryl, preferably comprising a five or six membered ring which may be substituted or unsubstituted and which may be carbocyclic or heterocyclic. It is preferred that R3 is monocyclic.
Where R3 is a five-membered ring, it is preferred that R3 is an N, O or S-containing heterocyclic ring, preferably a thienyl, furyl pyrrolyl or thiazolyl group, more preferably a thienyl group. Where R3 is a six-membered ring it is preferred that R3 is phenyl or an N-containing heterocyclic ring, preferably pyridyl.
Where R3 is substituted, it is preferred that R3 is substituted by substituent group(s) selected from halogen, preferably fluoro, chloro and bromo, more preferably chloro; lower alkyl, preferably methyl; lower alkoxy, preferably methoxy; nitro; and amino, preferably dialkylamino, more preferably dimethylamino.
In a particularly preferred embodiment, R3 is selected from thienyl, furyl, pyridyl (preferably 2-pyridyl) and phenyl, preferably 2-thienyl. Where R3 is selected from 2-thienyl, the 2-thienyl group is preferably unsubstituted or substituted by lower alkyl (preferably methyl) or halogen (preferably chloro or bromo, preferably chloro) or lower alkoxy preferably methoxy), and more preferably is unsubstituted or substituted by lower alkyl (preferably methyl), and is more preferably unsubstituted. Where R3 is selected from furyl, the furyl group is preferably a 2-furyl group and is preferably unsubstituted or substituted by lower alkyl (preferably methyl).
In the compounds of the present invention, preferably R5 is selected from hydrogen, alkyl, halogen, hydroxy, nitro, cyano, alkoxy, aryloxy, COR7, OCOR7, CO2R7, SR7, SOR7, SO2R7, SO2NR7R9, CONR7R9, CONR7NR8R9, OCONR7R8, NR7R8, NR7COR8, NR7CONR8R9, NR7CO2R8, NR7SO2R8, CR7xe2x95x90NOR8, NR7CONR8NR9R10, NR7NR8CO2R9, NR7NR8CONR9R10, SO2NR7NR8R9, NR7SO2NR9R9, NR7NR8SO2R9, NR7NR8COR9, NR7NR8R9, NR7CSNR8R9, or together with P6 forms a 5, 6 or 7 membered carbocyclic or heterocyclic ring.
In one embodiment of the present invention, R5 is selected from hydrogen, halogen, alkyl and aryl.
Where R5 is selected from aryl, it is preferred that R5 is an aryl group other than phenyl or an N-containing heteroaromatic group, particularly pyridyl, pyrazinyl pyrimidinyl and pyridazinyl. Where R5 is an aryl group, it is preferred that R5 is an aryl group selected from an Oxe2x80x94 or S-containing heterocyclic ring, preferably an O-containing ring, and preferably a 5-membered heterocyclic ring, preferably furanyl or thienyl, and more preferably furanyl.
In the compounds of the present invention, preferably R5 is selected from hydrogen, halogen and alkyl, and preferably R5 is hydrogen.
In the compounds of the present invention, it is preferred that R6 is selected from hydrogen, alkyl, aryl and halogen, and preferably R6 is hydrogen.
It is preferred that at least one, and preferably both of R5 and R6 are hydrogen. Where R5 and/or R6 are selected from alkyl, it is preferred that R5 and/or R6 are methyl.
Where any of R1, R2, or R4 to R6 are independently selected from NR7CO2R8, it is preferred that R9 is selected from alkyl and aryl.
Where any of R1, R2 or R4 to R6 are independently selected from NR7NR8CO2R9, it is preferred that R9 is selected from alkyl and aryl.
Where R4 is selected from NR7YNR8CO2R9, it is preferred that R9 is selected from alkyl and aryl.
In the compounds of the present invention where R4 is an NR7R8 group, the R7 and R8 groups may together form a ring to produce a cyclic amino group. The cyclic amino group is a saturated or partially unsaturated cyclic group (i.e. it is non-aromatic), and is preferably a saturated cyclic amino group. The cyclic amino group is preferably a 5-, 6- or 7-membered and is preferably a 5- or 6-membered cyclic amino group. Where partially unsaturated, it is preferred that only 1 double bond is present. The cyclic amino group may contain one or more additional heteroatoms, preferably one or two heteroatoms, wherein the heteroatoms are preferably selected from N, O and S and preferably from N and O. The cyclic amino groups may be substituted or unsubstituted, preferably substituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include any of those set out above in respect of the first and second embodiments. Preferably the cyclic amino groups are selected from pyrrolidinyl pyrrolidinonyl, piperidinyl, piperazinyl and morpholinyl groups, more preferably from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups, and particularly from pyrrolidinyl groups (preferably substituted and preferably substituted by hydroxy, lower alkyl or hydroxy(lower alkyl)).
In one embodiment of the present invention, R4 is preferably selected from alkyl (including trifluoromethyl); halogen (preferably chloro); alkoxy (preferably methoxy or ethoxy); SR7 (preferably alkylthio, preferably methylthio); dialkylamino (preferably dimethylamino); and monoalkylamino, wherein said alkyl groups are substituted or unsubstituted. In this embodiment, preferably R4 is unsubstituted alkyl, trifluoromethyl or monoalkylamino (wherein the alkyl groups are substituted or unsubstituted), and more preferably monoalkylamino (preferably NR7R8 wherein R7 is hydrogen, and R8 is substituted or unsubstituted). In this embodiment, where R4 is monoalkylamino or dialkylamino, the alkyl group(s) may be substituted as described above, for instance, by hydroxy, alkoxy, amino or dialkylamino.
Where R4 is alkyl, it is preferred that R4 is unsubstituted alkyl (preferably saturated alkyl, preferably lower alkyl) or halo-substituted alkyl (preferably trifluoromethyl).
In a particularly preferred embodiment of the invention, R4 is NR7R8. Where R4 is NR7R8, it is preferred that R7 is lower alkyl or hydrogen, and preferably hydrogen. Preferably, R8 is lower alkyl (substituted or unsubstituted and, where substituted, is preferably substituted by hydroxy, alkoxy, a saturated heterocyclic group or aryl (particularly heteroaryl)), cyclic alkyl or aryl.
In a further preferred emdbodment, R4 is NH2.
Where R4 is NR7NR8R9, it is preferred that R7 is hydrogen. Preferably R5 and R9 are also hydrogen.
In the compounds of formula (I), preferably R4 is selected from aklyl (including trifluoromethyl); halogen (preferably chloro); alkoxy (preferably methoxy or ethoxy, SR7 (preferably methylthio); and a substituted amino group (preferably NR7R8, NR7N8COR9, NR7NR8CO2R9, NR7CO2R8, NR7NR8CONR9R10, NR7NR8SO2R9, NR7N8CSNR9R10, NR7NR8R9 and NR7COR8, and more preferably NR7R8). Preferably R4 is a substituted amino group or alkyl. Most preferably R4 is a substituted amino group, preferably NR7R8 wherein R7 is hydrogen:
In the compounds of formula (Ia), preferably R4 is selected from alkyl (including trifluoromethyl); halogen (preferably chloro); alkoxy (preferably methoxy or ethoxy, SR7 (preferably methylthio); and a substituted amino group (preferably NR7R8, NR7YR8, NR7YNR8COR9, NR7YNR8CO2R9, NR7ZCO2R8, NR7YNR8CONR9R10, NR7YNR8SO2R9, NR7YNR8CSNR9R10, NR7NR8R9 and N(COR8)COR9, and more preferably NR7R8). Preferably R4 is a substituted amino group or alkyl. Most preferably R4 is a substituted amino group, as detailed below.
In the compounds of formulae (I) or (Ia), in a preferred embodiment where R4 is selected from NR7R8, it is preferred that R7 is hydrogen or alkyl, and preferably hydrogen, and R8 is selected from alkyl (preferably saturated alkyl), preferably lower alkyl (preferably saturated lower alkyl), substituted or unsubstituted and preferably substituted, wherein the preferred substituent groups on R8 are selected from aryl (preferably thienyl, furyl, pyridyl and phenyl); oxygen-containing groups, particularly alcohols (preferably hydroxy), ethers (preferably alkoxy); acids (preferably carboxy); acid derivatives (particularly (esters preferably alkoxycarbonyl), amides (preferably alkylcarbonylamino and arylcarbonylamino), carbamates (preferably alkoxycarbonylamino and arylalkoxycarbonylamino) and ureas (preferably alkylaminocarbonylamino, arylaminocarbonylamino and arylalkylaminocarbonylamino); nitrogen-containing groups, particularly amines and thioureas; and saturated heterocyclic groups, particularly N- and O-containing groups (preferably tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl and morpholinyl groups).
In the compounds of formulae (I) or (Ia), in an alternative preferred embodiment where R4 is selected from NR7R8, it is preferred that R7 is hydrogen or alkyl and preferably hydrogen, and R8 is selected from alkyl (preferably saturated alkyl), preferably lower alkyl (preferably saturated lower alkyl), substituted or unsubstituted and preferably substituted, wherein the preferred substituent groups on R8 are selected from aryl (preferably phenyl); oxygen-containing groups, alcohols (preferably hydroxy), ethers (preferably alkoxy) and acid derivatives, particularly esters (preferably alkoxycarbonyl) and carbamates (preferably alkoxycarbonylamino); nitrogen containing groups, particularly amines; and heterocyclic groups, particularly saturated N-containing heterocyclic groups (preferably pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl and morpholinyl groups).
In the compounds of formula (Ia) where R4 is NR7YNR8COR9, it is preferred that R7 is hydrogen. Preferably R8 is also hydrogen. Preferably R9 is selected from lower alkyl, cyclic alkyl and aryl (preferably substituted or unsubstituted phenyl or thienyl).
In the compounds of formula (Ia) where R4 is NR7YNR8CO2R9 or NR7YNR8SO2R9, it is preferred that R7 is hydrogen. Preferably R8 is also hydrogen. It is preferred that R9 is selected from lower alkyl (substituted or unsubstituted and, where substituted, preferably substituted by halogen (preferably chloro) or aryl).
In the compounds of formula (Ia) where R4 is NR7YNR8CONR9R10 or NR7YNR8CSNR9R10, it is preferred that R7 is hydrogen. Preferably R8 and R9 are also hydrogen. It is preferred that R10 is lower alkyl (substituted or unsubstituted), cyclic alkyl or aryl.
In the compounds of formula (Ia) where R4 is NR7ZCO2R8, preferably R7 is hydrogen and R8 is selected from hydrogen and lower alkyl, and preferably from lower alkyl.
In the compounds of formula (Ia) where R4 is NR7YR8, it is preferred that R7 is hydrogen. R8 is aryl, preferably substituted by lower alkyl, lower alkoxy and nitro.
In the compounds of formula Ia) where R4 is N(COR8)COR9, it is preferred that R8 and R9 are independently selected from lower alkyl.
In the compounds of formula (Ia), preferably Y is a saturated (alkylene) C2 to C4 carbon chain and is preferably unbranched. Preferably, Y is a C2 or C3 carbon chain, preferably a C2 carbon chain. Preferably, Y is a divalent CH2CH2 radical.
In the compounds of formula (Ia), preferably Z is a saturated (alkylene) C1 to C4 carbon chain and is preferably unbranched . Preferably, Z is a C1,C2 or C3 carbon chain, preferably a C2 carbon chair Preferably, Z is a divalent CH2CH2 radical.
In a particularly preferred embodiment of the invention, the compounds of the present invention are selected from:
(2R)-2-(1-Hydroxy-2-propylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
2-(3-(1H-Imidazol-1-yl)propylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
(2RS)-2-(1-Hydroxy-2-propylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
2-(3-Hydroxypropylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
3-Methyl-N-(2-(4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidin-2-yl)aminoethyl)butanamide,
Methyl (2-(4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidin-2-yl)aminoethyl)carbamate,
2-(2-(1H-Imidazol-4-yl)ethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
(2RS)-2-(2,3-Dihydroxypropylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
(2R)-2-(2-Hydroxypropylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
2-(2-Hydroxyethylamino)thieno[3,2-d]pyrimidin-4-yl 3-methyl-2-thienylmethanone,
2-Chloroethyl (2-(4-(2-thienylcarbonyl)thieno[3,2d]pyrimidin-2-yl)aminoethyl)carbamate,
(2S)-2-(1-Hydroxy-2-propylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
2-(3-(1H-Imidazol-1-yl)propylamino)thieno[3,2-d]pyrimidin-4-yl 3-methyl-2-thienylmethanone,
N-(2-(4-(2-Thienylcarbonyl)thieno[3,2-d]pyrimidin-2-yl)aminoethyl)cyclohexylcarboxamide,
Ethyl 4-(4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidin-2-ylamino)butanoate,
2-(2-Pyridylmethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
(2S)-2-(2-Hydroxypropylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
N-Allyl-Nxe2x80x2-(2-(4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidin-2-yl)aminoethyl)urea,
N-(2-(4-(2-Thienylcarbonyl)thieno[3,2-d]pyrimidin-2-yl)aminoethyl)acetamide,
2-(Tetrahydrofuran-2-ylmethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
N-Benzyl-Nxe2x80x2-2-(4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidin-2-yl)aminoethyl)urea,
2-(2-Hydroxyethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
Benzyl (2-(4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidin-2-yl)aminoethyl)carbamate, and
2-Aminothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone.
In an alternative embodiment, the compounds of the present invention are selected from:
2-thienyl 2-trifluoromethylthieno[3,2-d]pyrimidin-4-ylmethanone,
2-(2-hydroxyethyl)aminothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
2-ethylaminothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
2-ethylthieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone,
2-methylaminothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone, and
2-(2-methoxyethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone.
Where chiral the compounds of the present invention may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.
According to a further aspect of the invention, there is provided for use in therapy a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof.
The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject
The disorders of particular interest are those in which the blocking of purine receptors, partiucularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial. These may include movement disorders such as Parkinson""s disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson""s disease (punch-drunk syndrome).
Other movement disorders in which the blocking of purine receptors, may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders of the basal ganglia which result in abnormal movement or posture. The present invention may also be effective in treating Parkinson""s with on-off phenomena; Parkinson""s with freezing (end of dose deterioration); and Parkinson""s with prominent dyskinesias.
The compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L-DOPA, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
Other disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors may be beneficial include acute and chronic pain; for example neuropathic pain, cancer pain, trigeminal neuralgia, migraine and other conditions associated with cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord injury pain, central pain, post-herpetic pain and HIV pain; affective disorders including mood disorders such as bipolar disorder, seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease; central and peripheral nervous system degenerative disorders including corticobasal degeneration, demyelinating disease (multiple sclerosis, disseminated sclerosis), Freidrich""s ataxia, motoneurone disease (amyotrophic lateral sclerosis, progressive bulbar atrophy), multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathy (diabetic neuropathy, tabes dorsalis, drug-induced neuropathy, vitamin deficiency), systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy, spasticity; cognitive disorders including dementia, Alzheimers Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntingtons Disease, Lewy body dementia, senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome, dementia pugilans; central nervous system injury including traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injury, raised intracranial pressure, cerebral oedema, hydrocephalus, spinal cord injury; cerebral ischaemia including transient ischaemic attack, stroke (thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke, lacunar stroke) subarachnoid haemorrhage, cerebral vasospasm, neuroprotection for stroke, peri-natal asphyxia, drowning, cardiac arrest, subdural haematoma; myocardial ischaemia; muscle ischaemia; sleep disorders such as hypersomnia; eye disorders such as retinal ischaemia-reperfusion injury and diabetic neuropathy; cardiovascular disorders such as claudication; and diabetes and it""s complications.
According to a ether aspect of the present invention, there is provided the use of a compound of the present invention or a pharmaceutically acceptably salt or prodrug thereof in the manufacture of a medicament for the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A2A receptors, may be beneficial.
According to a further aspect of the present invention there is provided a method of treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial, the method comprising administration to a subject in need of such treatment an effective dose of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof.
The disorder may be caused by the hyperfunctioning of the purine receptors.
According to a further aspect of the present invention there is provided use of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment or prevention of movement disorders in a subject.
According to a further aspect of the invention there is provided a method of treating or preventing movement disorders comprising administration to a subject in need of such treatment an effective dose of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof.
According to a further aspect of the invention there is provided use of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for neuroprotection in a subject.
According to a further aspect of the invention there is provided a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof.
The medicament for or method of neuroprotection may be of use in the treatment of subjects who are suffering from or at risk from a neurodegenerative disorder, such as a movement disorder.
According to a further aspect of the invention, there is provided a method of preparing the novel compounds of the present invention. Compounds of the present invention (according to formula (I) or formula (Ia)) may be prepared according to conventional synthetic methods, such as set out in Reaction Scheme 1. 
Alcohols (5) are prepared from ketones (4) either by reduction using standard methods such as NaBH4 (where R2 is H) or by addition of, for example, Grignard reagents (where R2 is alkyl or aryl). Ketones (4) are prepared from chloro compounds (3) by known methods such as the addition of the appropriate aldehyde R3CHO and a base such as NaH in the presence of a catalyst such as N,N-dimethylimidazolium iodide (Miyashita A. et al., Heterocycles, 1997, 45, 2159-2173). Chloro compounds (3) are either known or are prepared from alcohols (2) by standard methods such as treatment with POCl3. Alcohols (2) are either known compounds or may be prepared by standard literature methods. Compounds of formula (3) where R4 is a chloro group are either known or are prepared from compounds of formula (2) where R4 is a hydroxy group by standard methods such as treatment with POCl3. Compounds of formula (2) where R4 is a hydroxy group are either known or are prepared by standard literature methods.
Oximes (6) are prepared from ketones (4) by standard methods such as treatment with the appropriate hydroxylamine in the presence of a base such as pyridine.
Compounds of formula (1) where R1 is a nitrile, alkoxycarbonyl, nitro, sulphonyl or amide group are prepared from chloro compounds (3) by standard methods such as the addition of a compound of formula HCR1R2R3, where R1 is a nitrile, alkoxycarbonyl, nitro, sulphonyl or amide group, in the presence of a base such as NaH.
Compounds of formula (1) where R1 is a hydroxymethyl group are prepared from compounds of formula (1) where R1 is an alkoxycarbonyl group by standard methods such as reduction with, for example, DIBAL.
Compounds of formula (1) where R4 is an alkoxy, aryloxy, hydroxy, alkylthio, arylthio, amino, mono or dialkylamino, cyano, carboxamido or substituted or unsubstituted hydrazino group may be prepared from compounds of formula (1) where R4 is a halogen by standard methods such as reaction with the appropriate nucleophile. Appropriate nucleophiles would include for example alkoxides, aryloxides, hydroxide, alkylthiolates, arylithiolates, ammonia, mono or dialkylamines, cyanide, carboxamide salts, hydrazine and substituted hydrazines. Alternatively compounds of formula (1) where R4 is an amino group may be prepared from compounds of formula (1) where R4 is a halogen by standard methods such as reaction with an appropriately protected amino compound to form a compound of formula (1) where R4 is a protected amine, followed by removal of the protecting group by standard methods. Appropriate protecting groups may include, for example, benzyl, dimethoxybenzyl, trialkylsilyl or trifluoroacetyl groups.
Compounds of formula (1) where R4 is an acyloxy, carbamate, acylamino, semicarbazide, thiosemicarbazide, sulphonamide, urea, thiourea, sulphamide, acylhydrazine or sulphonylhydrazine group may be prepared by derivatisation of the corresponding compound of formula (1) where R4 is a hydroxy, mercapto, amino, monoalkylamino or hydrazino group using standard literature methods.
Compounds of formula (1) where R4 is a sulphonyl or sulphinyl group may be prepared from compounds of formula (1) where R4 is an alkylthio or arylthio group by standard methods such as oxidation with an appropriate reagent.
Compounds of formula (1) where R4 is a group containing an amino substituent, for example an aminoalkyl group or an aminoalkylamino group such as an ethylenediamine group, may be further derivatised using standard methods as described above. For example the amino group may be converted into an alkylamine, amide, carbamate, urea, thiourea, sulphonamide or sulphamide by using standard literature methods such as alkylation, reductive alkylation, acylation, sulphonylation or reaction with an appropriate isocyanate.
Compounds of formula (1) where R4 is an ester, amide or hydrazide may be prepared from compounds of formula (1) where R4 is a halogen by standard methods such as carbonylation reactions. Alternatively compounds of formula (I) where R4 is an ester group may be prepared from compounds of formula (2) where R4 is an ester group by the methods described above. Compounds of formula (2) where R4 is an ester group are known in the literature. Further modification of a compound of formula (1) where R4 is an ester or amide can lead, by using standard literature methods, to compounds of formula (1) where R4 is for example an aldehyde, carboxylic acid, oxime, amidine, hydroxyalkyl, or aminoalkyl group. Further modification of a compound of formula (1) where R4 is an ester, amide, hydrazide, amidine, aldehyde or carboxylic acid can lead, by the use of standard literature methods, to compounds of formula (1) where R4 is, for example a 5- or 6-membered heterocyclic group such as oxadiazole, thiadiazole, thiazole, oxazole, isoxazole, pyrazole, triazole, imidazole or pyrimidine.
Compounds of formula (1) where R1 is an alkoxy, acyloxy or carbamate group may be prepared from compounds of formula (1) where R1 is a hydroxy group by standard methods such as alkylation, acylation or by reaction with an appropriate isocyanate.
Compounds of formula (1) where R1 is an amino, alkylamino, acylamino, sulphonylamino, urea or sulphamide may be prepared from compounds of formula (1) where R1 is an amino group by standard methods such as alkylation, acylation, sulphonylation or by reaction with an appropriate isocyanate.
Compounds of formula (1) where R1 is an amino group may be prepared from a compound of formula (1) where R1 is a nitro group by standard methods such as reduction. Alternatively compounds of formula (1) where R1 is an amino group may be prepared from a compound of formula (1) where R1 and R2 together form a carbonyl group by standard methods such a reductive amination.
Compounds of formula (1) where R1 is a hydrazino group may be prepared from compounds of formula (1) where R1 is a hydroxy group by standard methods such as conversion of the hydroxy group into a suitable leaving group, for example a mesylate or tosylate group, followed by displacement with hydrazine or an appropriately substituted hydrazine. Further derivatisation of the hydrazine group, if required, may be achieved by standard methods such as for example acylation or sulphonylation.
Compounds of formula (1) where R1 and R2 together form an imine group (Cxe2x95x90Nxe2x80x94R11) or a hydrazone group (Cxe2x95x90NNR11R12) may be prepared from compounds of formula (4) by standard methods such as treatment with the appropriate amine or hydrazine.
Compounds of formula (1) where R5 is an aryl (including heteroaryl) group may be prepared from compounds of formula (1) where R5 is a halogen by standard methods such as a palladium catalysed aryl coupling reaction such as a Suzuki coupling or a Stille coupling reaction. Compounds of formula (1) where R5 is a halogen are prepared from compounds of formula (3) where R5 is a halogen according to Reaction Scheme 1. Compounds of formula (3) where R5 is a halogen are known in the literature.
Compounds of formula (1) where R5 is an amino group may be prepared from compounds of formula (1) where R5 is a nitro group by standard methods such as reduction. Further modification of compounds of formula (1) where R5 is an amino group can lead, by the use of standard methods, to compounds of formula (1) where R5 is an alkylamino, acylamino, carbamate, urea, thiourea, sulphonamide or sulphamide group as described above. Compounds of formula (1) where R5 is a nitro group may be prepared from compounds of formula (3) where R5 is a nitro group according to Reaction Scheme 1. Compounds of formula (3) where R5 is a nitro group are known in the literature.
According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the present invention in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of the present invention with a pharmaceutically acceptable carrier or excipient.
The pharmaceutical compositions employed in the present invention comprise a compound of the present invention, or pharmaceutically acceptable salts or prodrugs thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients known to those skilled in the art. The term, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d, refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
Where the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.
Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of the present invention. For example, oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like. The most suitable route in any given case will depend on the severity of the condition being treated. The most preferred route of administration of the present invention is the oral route. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practical use, the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.
Pharmaceutical compositions employed in the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practised without departing from the purpose and interest of this invention.